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Basic principles of the
safety assessment of drugs
Björn Dahl, PhD Senior Project Director
Global Safety Assessment
AstraZeneca R&D
SFT Annual meeting 2013
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Outline of presentation
Safety assessment in the discovery and development of drugs
2
Target
Selection PoM/PoP/PoC DFL Launch LCM
Lead
Optimisation
Lead
Generation
Target
Lead chemistry
Cmpd selection
Cmpd characterisation / regulatory
documentation / risk assessment
New indications,
formulations,
combinations,
impurities,
degradation
products, patient
populations,
paediatrics etc
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Target Safety Assessment
Some components • overall target function/biology in health and disease
• pathway mapping/interaction with other pathways • information from ko/ transgenic models • human target variations - implications
• target distribution
• explicitly not only confined to intended pharmacological tissue/ organ • identifying relevant species for toxicological characterisation • in health and in disease
• functionally / structurally related targets
• selectivity (off target pharmacology)
critical issues addressed experimentally when possible
build/refine safety plans moving forward
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Chemistry Safety Assessment
Components of early avoidance of chemical
structure safety liabilities:
• chemical structures are analysed continuously in silico for possible
structure-related safety concerns:
• genotoxicity
• hERG channel blockade
• reactive metabolite formation
• phospholipidosis
• bone marrow toxicity
• structural similarity to problematic molecules
• DMPK properties
• and more ……
experimental follow up of potential issues
build/refine safety plans moving forward
4
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Optimisation of lead compounds Screening in vitro for e.g.
• Genotoxicity • hERG and other ion channels • Cyto tox • Immunotox • Hepatic tox • Bone marrow tox • Transporters • Metabolism/CYPs • Reactive metabolites • Off target pharmacology/secondary pharmacology • Cross-species comparisons where applicable
Fit for purpose in vivo studies, e.g.
• To early address target or chemistry related safety concerns
identified • To extract relevant safety information as part of PK/PD
characterisation in in vivo (disease) models • To build confidence in safety before expanding into larger
regulatory animal studies Internal decision making up to this point
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Safety characterisation of candidate drug
Objective - Provide and assess safety information relevant for
conducting safe clinical trials and supporting marketing applications.
Animal data generally more in focus at: - First dose to man (healthy volunteers, patients) - Increased duration/doses - First dose to women of childbearing potential - First dose to children - Assessing reproductive and carcinogenic risks
Clinical safety data evolve during development and eventually override some of the toxicology data Drug safety surveillance of marketed drugs continues for the life-time of the products
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Regulatory guidelines - framework
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• International Conference on
Harmonisation of Technical
Requirements for Registration of
Pharmaceuticals for Human Use (ICH)
• ICH M3(R2) Guidance on nonclinical
safety studies for the conduct of
human clinical trials and marketing
authorisation for pharmaceuticals
• And many more detailed international
and regional guidances
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Considerations selecting animal species
• Pharmacologically responsive? • To address concerns around exaggerated pharmacology
• Appropriate local and systemic exposure to the drug • Ensure adequate exposure margins in the relevant tissues/compartments is
achievable using the proposed route of administration in man.
• Supplement by alternative route if needed and feasible
• Take into account local vs systemic exposure, half-life, exposure profiles,
max/min levels, protein binding etc.
• Coverage of human relevant metabolites? • Compare cross-species including man
• Microsomes
• Hepatocytes
• In vivo data
8
RT: 1.98 - 11.48
2 3 4 5 6 7 8 9 10 11 Time (min) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Rela
tive A
bundance
M1
0
M
7
M1
1 M1
8 M3
9
M1
2
RT: 1.98 - 11.48
2 3 4 5 6 7 8 9 10 11 Time (min) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Rela
tive A
bundance
M1
0
M
7
M1
1
M1
2 M3
9
M1
8
RT: 1.98 - 11.48
2 3 4 5 6 7 8 9 10 11 Time (min) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Rela
tive A
bundance
M1
0
M1
1 M1
2 M1
8 M3
9
M
7
Chromatograms obtained from analysis of Human, Rat and Dog steady state plasma samples
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Safety Pharmacology
Studies that investigate the potential undesirable pharmacodynamic effects on
physiological functions at exposures in the therapeutic range and above
• Studies on the mode of action and or effects in relation to the desired therapeutic target
• Studies on the mode of action and/or effects not related to the desired therapeutic target
(with focus on vital functions such as CV, Respiratory, CNS)
• Usually single dose/short-term studies in rodents and non-rodents
• Identify undesirable pharmacodynamic properties relevant to human safety
• Evaluate adverse pharmacodynamic effects observed in toxicology and/or
clinical studies
• Investigate mechanisms of adverse pharmacodynamic effects
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General toxicity studies
One rodent and one non-rodent species - Generally rats and dogs - Duration equal or longer than intended clinical trial (up
to 6 months in rodents and 9/12 months in non-rodents)
Dose levels:
- Relevant route of administration - Therapeutic up to Max Tolerable/Limit/Fesible Dose - Exposure rather than dose levels - Generally 1 control and 3 treatment groups (+ recovery)
Aim:
- Systemic exposure levels - Target(s) of toxicity - Incidences and severities - Dose-dependency - Time-dependency - Species specificity - Reversibility
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General toxicity studies continued
Evaluations - endpoints
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• clinical signs
• body weight
• food & water consumpt.
• ophthalmoscopy
• ECG (non-rodents)
• toxicokinetics
• clinical pathology
• haematology
• blood chemistry
• urinalysis
• pathology
• necropsy/gross pathology
• organ weights (12-20)
• microscopic pathology (40-45 different tissues from each animal)
• ad hoc as appropriate
• non std biomarkers
• special stainings
• male fertility
• explorative samples
• Met ID
• safety pharm endpoints
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Genetic toxicology
Drug: in vitro assays
- Ames Test (bacteria) – gene mutation
- Mouse Lymphoma TK locus test or Chromosomal aberrations in human lymphocytes (mammalian cells) – chromosomal damage
- +/- metabolic activation system in vivo assays
- Micronucleus assay (rats or mice, bone marrow)
Genotoxic Impurities:
- In silico and in vitro assessment of Potential Genotoxic Impurities (PGI) from manufacturing route or degradation processes
- Control under Threshold of Toxicological Concern (TTC) (some times down to ppm levels of active drug)
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Reproductive toxicology
• Fertility – dosing of males and females before and during mating, but also evaluation of reproductive organs in general tox studies: usually in rats
• Embryofoeteal development – dosing of females during major organ development – evaluation of offspring: usually in rats and rabbits
• Peri and postnatal development: including reproductive performance of offsping (2nd generation)
• Generally, studies on fertility and embryofoetal development before inclusion of women of childbearing potential although exceptions do exist
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Carcinogenicity
• Studies in rodents with life time exposure ~ 2 years
• Usually rats and mice (2 studies)
• 500-600 animals/study
• Tumour incidence – histopathological evaluation of most tissues
• Performed at a late stage of development – takes ~3 years to complete
• Options for alternative tests, eg 6 month test in transgenic mice models sensitive to tumour development
• Can replace one of the studies
• ICH S1 revision under discussion
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Phototoxicity
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Assessment for potential phototoxicity part of the standard package
• Does the cmpd absorb UV/VIS light in significant amounts (MEC>1000)?
• Does it distribute to tissues exposed to sunlight?
• In vitro assessment
• In vivo assessment
Apply precautions if needed in clinical trials
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Safety margins - Risk assessment
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Safety margin: 10x
Correction free fraction (unbound): 7.5x
0.6
Estimated pharmacodynamic Estimated pharmacodynamic
responseresponse
(Human, fri fraction 13%)(Human, fri fraction 13%) Effect parameter
Toxicological responseToxicological response
(dog, fri fraction 10%)(dog, fri fraction 10%)
Drug koncentration
(µM)
6 70
0.08 0.6 7
total
unbound
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Primary PK parameters in animals (CV% )
CL
mL/min/kg
VDss
mL/kg
t1/2, 2
(h)
Cynomolgus
monkey
3.6 (45) 87 (24) 19.4 (47)
Mouse 12 (8) 138 (13) 10.2 (12)
Rat 5.6 (5.4) 73 (9.4) 11 (16)
Rat a)
5.7 (13) 77 (22) 11 (40)
Predicted human PK
CL (mL/h/kg)
Vss
(mL/kg)
t1/2, 2
(h)
Human* 1.5 53 29
* Predicted from allometric scaling
y = 0.741x + 0.643
-1
-0,5
0
0,5
1
1,5
2
2,5
-2,00 -1,00 0,00 1,00 2,00 3,00
log
(CL
)Log (BW)
mousemouse
ratrat
cynocyno
HomoHomo
Pharmacokinetic models – allometric scaling – predictions to man
11
22
33
Example prediction of human exposure at FTIM
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What is an appropriate safety margin/exposure limit?
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Some general considerations: - Patient population, indication - Human relevance or not - Human vs animal sensitivity - Exaggerated pharmacology or unspecific toxicology - Adaptive vs. degenerative - Reversibility - Biomarker sensitivity and predictivity, if available
- Risk to occur in the study population at suggested dose levels? - Potential consequences if it occur? - Risk/benefit for the patients? - How to detect, predictive or diagnostic markers available? - How to act if it occur, recovery following drug withdrawal, antidotes?
Acceptable safety margins and exposure limits set case-by-case Risk assessment not only for next clinical trial but also for ”line of sight”
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Concordance of toxicity: animal vs man
19 Olsson et al., Regulatory Toxicology and Pharmacology 32, 56-67 (2000)
0
20
40
60
80
100
120
140
160
Non-
rodent
only
Non-
rodent +
rodent
Rodent
only
Any
species
No
species
No
of
hu
ma
n t
ox
icit
ies
27% 29%
71%
7%
36%
0
20
40
60
80
100
120
140
Dog Primate Rat Mouse G. pig
No
of
hu
ma
n t
ox
icit
ies
Concordance
Non-concordance
0
10
20
30
40
50
60
1 day 1 week 2 week 1 month 2-3
month
6 month
No
of
hu
man
to
xici
ties
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20
Sola dosis facit venenum
“The dose makes the poison”